The results of recent studies indicated that opioid agonists that selectively act via .delta. receptors should have advantages over currently available opioid analgesics. In particular, potential advantages include the production of analgesia with
i) decreased (or no) development of physical dependence (A. Cowan et al., J. Pharmacol. Exp. Ther. 246, 950-955 (1988)); PA1 ii) no depression (and the possible stimulation) of respiratory function (P. Y. Cheng et al., Eur. J. Pharmacol. 230, 85-88 (1993)); and PA1 iii) little or no adverse gastrointestinal effects (J. J. Galligan et al., J. Pharmacol. Exp. Ther. 229, 641-648 (1984). PA1 R.sub.4 and R.sub.5 are both H, whereas R.sub.3 and R.sub.6 are both C.sub.1 -C.sub.6 alkyl; or PA1 R.sub.3, R.sub.5, R.sub.6 are all H, whereas R.sub.4 is F, Cl, Br, I, OH, NO.sub.2 or NH.sub.2 ; PA1 R.sub.7 is a 2-phenylethyl- or a 2-cyclohexylethyl group containing one or more additional substituents in ortho- or para-position of the ring moiety or at the carbon atom adjacent to the ring moiety; for the manufacture of a medicament for use in the treatment of pain. PA1 R.sub.9 is selected from H, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 OH, and phenyl; ##STR6## wherein R.sub.10 and R.sub.11 is each and independently selected from H, N02, NH.sub.2, F, Cl, Br, I, and C.sub.1 -C.sub.6 alkyl; ##STR7## wherein R.sub.12 is selected from anyone of C.sub.1 -C.sub.6 alkyl and --(CH.sub.2).sub.n --Ph, wherein n=0-3; ##STR8## wherein R.sub.13 and R.sub.14 is each and independently selected from anyone of H, C.sub.1 -C.sub.6 alkyl, and --(CH.sub.2).sub.n --Ph wherein n=0-3; ##STR9## PA1 R.sub.1 is selected from H and CH.sub.3 ; PA1 R.sub.2 is selected from H and CH.sub.3 ; PA1 R.sub.3 is selected from H and CH.sub.3 ; PA1 R.sub.4 is H; PA1 R.sub.5 is H; PA1 R.sub.6 is selected from H and CH.sub.3 ; PA1 R.sub.7 is selected from anyone of ##STR10##
Selective peptide .delta. agonists currently available include the enkephalin analogs H-Tyr-D-Thr-Gly-Phe-Leu-Thr-OH (DTLET; G. Gacel et al., J. Med. Chem. 31, 1891-1897 (1988)) and ##STR2## (DPDPE, H. I. Mosberg et al., Proc Natl. Acad. Sci. USA 80, 5871-5874 (1983) and the deltorphins (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH.sub.2 (dermenkephalin)), H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH.sub.2 (deltorphin I) and H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH.sub.2 (deltorphin II); V. Erspamer et al., Proc. Natl. Acad. Sci. USA 86, 5188-5192 (1989)). However, these peptides are of relatively large molecular size (molecular weight&gt;600) and for this reason their ability to cross the blood-brain barrier (BBB) is very limited.
Non-peptide .delta. agonists that have recently been developed include the racemic compound BW373U86 (K.-J. Chang et al., J. Pharmacol. Exp. Ther. 267, 852-857 (1993)) and its chemically modified enantiomer SNC80 (S.N. Calderon et al., J. Med. Chem. 37, 2125-2128 (1994)) as well as the compound TAN-67 (J. Kamei et al., Eur. J. Pharmacol. 276, 131-135 (1995)). However, BW 373U86 produced significant toxicity, manifested behaviorally as convulsions and barrel rolling, in mice (S. D. Comer et al., J. Pharmacol. Exp. Ther. 267, 888-895 (1993)), and TAN-67 showed no significant antinociceptive effect in the mouse tail flick test (J. Kamei et al., Eur. J. Pharmacol. 276, 131-135 (1995)). Therefore, there is still a need for the development of new potent .delta. opioid agonists of low molecular weight and high lipophilic character.
Peptides containing the N-terminal segment H-Tyr-Tic-Aaa (Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Aaa=aromatic or aliphatic amino acid residue) that are very potent and highly selective .delta. opioid antagonists have recently been disclosed by P. W. Schiller et al., in FASEB J. 6(4), A1575 (1992), at the International Narcotics Research Conference (INRC) Meetings in Keystone, CO, Jun. 24-29 (1992) and in Skovde, Sweden, Jul. 10-15 (1993), at the 2nd Japan Symposium on Peptide Chemistry, Shizuoka, Japan, Nov. 9-13 (1992), at the 22nd European Peptide Symposium in Interlaken, Switzerland, Sept. 9-13 (1992), at the 14th American Peptide Symposium in Columbus, Ohio, Jun. 18-23 (1995), in Proc. Natl. Acad. Sci. USA 89, 11871-11875 (1992), and in J. Med. Chem. 36, 3182-3187 (1993).
Recently, it has been found that dipeptide derivatives of the type H-Tyr-Tic-NH--(CH.sub.2).sub.n --Ph (Ph=phenyl) also have .delta. antagonist properties, if n=1, 3 or 4. In the case of n=2, however, the compound (H-Tyr-Tic-NH-CH.sub.2 --CH.sub.2 --Ph) surprisingly turned out to be a full, but only moderately potent .delta. agonist, as reported by P. W. Schiller et al. at the 23rd European Peptide Symposium in Braga, Portugal, Sept. 4-10, 1994.
Thus, the object of the present invention was to find structurally modified analogs of H-Tyr-Tic-NH--CH.sub.2 --CH.sub.2 --Ph with improved .delta. agonist potency. Compounds of this type should have potential for therapeutic use as centrally acting analgesics because their low molecular weight and lipophilic character can be expected to facilitate crossing of the BBB.